本文主要研究内容
作者谭欣同（2019）在《食品危害物丙烯酰胺影响机体生物节律的分子机制研究》一文中研究指出：生物节律是机体以24 h为周期的内在时间系统。生物钟有条不紊的调控着机体的生命活动,对维持代谢平衡,营养摄取以及机体健康起着重要作用。生物钟由位于下丘脑视交叉上核(Suprachiasmatic nucleus)的母钟和位于肝脏、肾脏和肠道等器官的子钟构成。食物信号是调控生物钟的重要授时因子,然而人体在摄食的过程中,不可避免的会摄入一些有毒有害物质,它们对机体生物钟系统存在一定影响,但具体的机制鲜有报道。丙烯酰胺是淀粉类食物在高温加工过程中经美拉德反应形成的一种食品危害物。研究表明,丙烯酰胺的毒性主要表现在神经毒性、肝脏毒性、遗传毒性和潜在的致癌性。基于此,本研究以典型的食品危害物丙烯酰胺为研究对象,以生物钟基因为靶点,通过体内体外实验探究了丙烯酰胺对机体生物钟系统的影响。主要研究内容如下:(1)以C57BL/6J小鼠为研究对象,通过饮水方式进行丙烯酰胺干预,探究了食品危害物丙烯酰胺对小鼠脑部生物钟的影响。结果显示,丙烯酰胺诱导了小鼠脑部生物钟基因节律震荡减弱及相位漂移,抑制了小鼠脑部海马区生物钟蛋白Bmal1和Clock的表达。Morris水迷宫结果显示丙烯酰胺加剧了小鼠夜间(ZT16)认知功能障碍和记忆损失。与行为学结果一致,丙烯酰胺干预在ZT16抑制了小鼠脑部海马区ERK/CREB/BDNF信号通路及突触后致密物SNAP-25和PSD-95的表达。同时,丙烯酰胺导致了小鼠海马区在夜间出现过度自噬的现象。此外,丙烯酰胺通过影响肠屏障的完整性,增加血液中LPS、IL-1β和TNF-α的水平进而加剧脑部炎症反应。(2)以C57BL/6J小鼠作为研究对象,探究丙烯酰胺对小鼠肝脏子钟生物节律的影响。结果显示,丙烯酰胺可以诱导小鼠肝脏子钟节律失调并且抑制生物钟蛋白Bmal1的表达。丙烯酰胺破坏了小鼠体内抗氧化体系的平衡,在夜间显著抑制小鼠体内GSH和SOD的含量。同时,丙烯酰胺影响了肝脏的线粒体形态动力学,上调肝脏线粒体分裂、融合和自噬相关基因的表达,进而加剧肝脏线粒体功能的损伤。最后,以HepG2细胞为研究对象,进一步验证了丙烯酰胺通过AKT信号通路和诱导氧化应激抑制了生物钟蛋白Bmal1和Sirt1的表达,探究了丙烯酰胺干预生物钟基因的分子机制。(3)以C57BL/6J小鼠作为研究对象,深入探讨高脂膳食加剧丙烯酰胺肝脏毒性中生物钟基因的参与机制。结果显示,高脂膳食小鼠在夜间(ZT12)摄入丙烯酰胺会显著降低小鼠的生存率且加剧了肝脏的线粒体损伤,导致线粒体形态肿胀,线粒体复合物酶表达的下降。此外,高脂膳食诱导的肝脏CYP2E1表达在ZT12异常升高导致丙烯酰胺向环氧丙酰胺的转化。同时,丙烯酰胺在ZT12会诱导小鼠肠道屏障的损伤,导致肠道内毒素的渗透,进而加剧系统性炎症。最后,核心生物钟基因Cry1通过调控NF-κB信号通路加剧了丙烯酰胺在夜间诱导的肝脏损伤。(4)以HepG2细胞和原代肝细胞为研究对象,探讨生物钟基因Bmal1在白藜芦醇改善丙烯酰胺诱导节律失调和线粒体损伤中的参与机制。结果显示,白藜芦醇可以有效干预丙烯酰胺诱导的原代肝细胞生物钟基因相位偏移及振幅减弱。同时,白藜芦醇处理可以改善丙烯酰胺诱导的线粒体损伤,减少细胞内活性氧含量,上调线粒体复合物酶I-IV的表达。白藜芦醇干预可以Bmal1依赖性的激活Nrf2信号通路,提高细胞内的抗氧化能力。最后,白藜芦醇可以通过生物钟基因Bmal1和Cry1改善丙烯酰胺诱导的线粒体功能损伤和炎症反应。综上所述,丙烯酰胺可以通过影响生物钟基因表达的节律性变化、损伤线粒体功能诱导了小鼠生物节律紊乱。研究还发现高热能膳食模式加剧了丙烯酰胺诱导的肝脏损伤及生物节律紊乱,而食品功能组分白藜芦醇可通过调节细胞氧化还原平衡改善丙烯酰胺诱导的生物节律紊乱。本研究揭示了食品危害物丙烯酰胺的毒理学新机制,并为食品功能组分通过改善机体生物节律失调的研究提供新的思路和理论依据。
Abstract
sheng wu jie lv shi ji ti yi 24 hwei zhou ji de nei zai shi jian ji tong 。sheng wu zhong you tiao bu wen de diao kong zhao ji ti de sheng ming huo dong ,dui wei chi dai xie ping heng ,ying yang she qu yi ji ji ti jian kang qi zhao chong yao zuo yong 。sheng wu zhong you wei yu xia qiu nao shi jiao cha shang he (Suprachiasmatic nucleus)de mu zhong he wei yu gan zang 、shen zang he chang dao deng qi guan de zi zhong gou cheng 。shi wu xin hao shi diao kong sheng wu zhong de chong yao shou shi yin zi ,ran er ren ti zai she shi de guo cheng zhong ,bu ke bi mian de hui she ru yi xie you du you hai wu zhi ,ta men dui ji ti sheng wu zhong ji tong cun zai yi ding ying xiang ,dan ju ti de ji zhi xian you bao dao 。bing xi xian an shi dian fen lei shi wu zai gao wen jia gong guo cheng zhong jing mei la de fan ying xing cheng de yi chong shi pin wei hai wu 。yan jiu biao ming ,bing xi xian an de du xing zhu yao biao xian zai shen jing du xing 、gan zang du xing 、wei chuan du xing he qian zai de zhi ai xing 。ji yu ci ,ben yan jiu yi dian xing de shi pin wei hai wu bing xi xian an wei yan jiu dui xiang ,yi sheng wu zhong ji yin wei ba dian ,tong guo ti nei ti wai shi yan tan jiu le bing xi xian an dui ji ti sheng wu zhong ji tong de ying xiang 。zhu yao yan jiu nei rong ru xia :(1)yi C57BL/6Jxiao shu wei yan jiu dui xiang ,tong guo yin shui fang shi jin hang bing xi xian an gan yu ,tan jiu le shi pin wei hai wu bing xi xian an dui xiao shu nao bu sheng wu zhong de ying xiang 。jie guo xian shi ,bing xi xian an you dao le xiao shu nao bu sheng wu zhong ji yin jie lv zhen dang jian ruo ji xiang wei piao yi ,yi zhi le xiao shu nao bu hai ma ou sheng wu zhong dan bai Bmal1he Clockde biao da 。Morrisshui mi gong jie guo xian shi bing xi xian an jia ju le xiao shu ye jian (ZT16)ren zhi gong neng zhang ai he ji yi sun shi 。yu hang wei xue jie guo yi zhi ,bing xi xian an gan yu zai ZT16yi zhi le xiao shu nao bu hai ma ou ERK/CREB/BDNFxin hao tong lu ji tu chu hou zhi mi wu SNAP-25he PSD-95de biao da 。tong shi ,bing xi xian an dao zhi le xiao shu hai ma ou zai ye jian chu xian guo du zi shi de xian xiang 。ci wai ,bing xi xian an tong guo ying xiang chang bing zhang de wan zheng xing ,zeng jia xie ye zhong LPS、IL-1βhe TNF-αde shui ping jin er jia ju nao bu yan zheng fan ying 。(2)yi C57BL/6Jxiao shu zuo wei yan jiu dui xiang ,tan jiu bing xi xian an dui xiao shu gan zang zi zhong sheng wu jie lv de ying xiang 。jie guo xian shi ,bing xi xian an ke yi you dao xiao shu gan zang zi zhong jie lv shi diao bing ju yi zhi sheng wu zhong dan bai Bmal1de biao da 。bing xi xian an po huai le xiao shu ti nei kang yang hua ti ji de ping heng ,zai ye jian xian zhe yi zhi xiao shu ti nei GSHhe SODde han liang 。tong shi ,bing xi xian an ying xiang le gan zang de xian li ti xing tai dong li xue ,shang diao gan zang xian li ti fen lie 、rong ge he zi shi xiang guan ji yin de biao da ,jin er jia ju gan zang xian li ti gong neng de sun shang 。zui hou ,yi HepG2xi bao wei yan jiu dui xiang ,jin yi bu yan zheng le bing xi xian an tong guo AKTxin hao tong lu he you dao yang hua ying ji yi zhi le sheng wu zhong dan bai Bmal1he Sirt1de biao da ,tan jiu le bing xi xian an gan yu sheng wu zhong ji yin de fen zi ji zhi 。(3)yi C57BL/6Jxiao shu zuo wei yan jiu dui xiang ,shen ru tan tao gao zhi shan shi jia ju bing xi xian an gan zang du xing zhong sheng wu zhong ji yin de can yu ji zhi 。jie guo xian shi ,gao zhi shan shi xiao shu zai ye jian (ZT12)she ru bing xi xian an hui xian zhe jiang di xiao shu de sheng cun lv ju jia ju le gan zang de xian li ti sun shang ,dao zhi xian li ti xing tai zhong zhang ,xian li ti fu ge wu mei biao da de xia jiang 。ci wai ,gao zhi shan shi you dao de gan zang CYP2E1biao da zai ZT12yi chang sheng gao dao zhi bing xi xian an xiang huan yang bing xian an de zhuai hua 。tong shi ,bing xi xian an zai ZT12hui you dao xiao shu chang dao bing zhang de sun shang ,dao zhi chang dao nei du su de shen tou ,jin er jia ju ji tong xing yan zheng 。zui hou ,he xin sheng wu zhong ji yin Cry1tong guo diao kong NF-κBxin hao tong lu jia ju le bing xi xian an zai ye jian you dao de gan zang sun shang 。(4)yi HepG2xi bao he yuan dai gan xi bao wei yan jiu dui xiang ,tan tao sheng wu zhong ji yin Bmal1zai bai li lu chun gai shan bing xi xian an you dao jie lv shi diao he xian li ti sun shang zhong de can yu ji zhi 。jie guo xian shi ,bai li lu chun ke yi you xiao gan yu bing xi xian an you dao de yuan dai gan xi bao sheng wu zhong ji yin xiang wei pian yi ji zhen fu jian ruo 。tong shi ,bai li lu chun chu li ke yi gai shan bing xi xian an you dao de xian li ti sun shang ,jian shao xi bao nei huo xing yang han liang ,shang diao xian li ti fu ge wu mei I-IVde biao da 。bai li lu chun gan yu ke yi Bmal1yi lai xing de ji huo Nrf2xin hao tong lu ,di gao xi bao nei de kang yang hua neng li 。zui hou ,bai li lu chun ke yi tong guo sheng wu zhong ji yin Bmal1he Cry1gai shan bing xi xian an you dao de xian li ti gong neng sun shang he yan zheng fan ying 。zeng shang suo shu ,bing xi xian an ke yi tong guo ying xiang sheng wu zhong ji yin biao da de jie lv xing bian hua 、sun shang xian li ti gong neng you dao le xiao shu sheng wu jie lv wen luan 。yan jiu hai fa xian gao re neng shan shi mo shi jia ju le bing xi xian an you dao de gan zang sun shang ji sheng wu jie lv wen luan ,er shi pin gong neng zu fen bai li lu chun ke tong guo diao jie xi bao yang hua hai yuan ping heng gai shan bing xi xian an you dao de sheng wu jie lv wen luan 。ben yan jiu jie shi le shi pin wei hai wu bing xi xian an de du li xue xin ji zhi ,bing wei shi pin gong neng zu fen tong guo gai shan ji ti sheng wu jie lv shi diao de yan jiu di gong xin de sai lu he li lun yi ju 。
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论文作者分别是来自西北农林科技大学的谭欣同，发表于刊物西北农林科技大学2019-07-11论文，是一篇关于生物钟论文,丙烯酰胺论文,线粒体功能紊乱论文,认知功能论文,白藜芦醇论文,西北农林科技大学2019-07-11论文的文章。本文可供学术参考使用，各位学者可以免费参考阅读下载，文章观点不代表本站观点，资料来自西北农林科技大学2019-07-11论文网站，若本站收录的文献无意侵犯了您的著作版权，请联系我们删除。
标签：生物钟论文; 丙烯酰胺论文; 线粒体功能紊乱论文; 认知功能论文; 白藜芦醇论文; 西北农林科技大学2019-07-11论文;